CA3094551C

CA3094551C - Extended release pharmaceutical composition containing fesoterodine and process for the preparation thereof

Info

Publication number: CA3094551C
Application number: CA3094551A
Authority: CA
Inventors: Agni GRYPIOTI; Panagiotis TSITSAS
Original assignee: Pharos Ltd; Rontis Hellas SA
Current assignee: Pharos Ltd; Rontis Hellas SA
Priority date: 2018-04-26
Filing date: 2018-04-26
Publication date: 2024-01-02
Anticipated expiration: 2038-04-26
Also published as: WO2019206391A1; CA3094551A1; EP3784217A1

Abstract

The present invention relates to an extended release pharmaceutical composition for oral administration comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite or derivative thereof, as an active ingredient, an effective quantity of glycerol dibehenate as a stabilizing agent in order to prevent the degradation and improve the physicochemical stability of the active ingredient in the finished dosage form and at least one pharmaceutically acceptable excipient as a rate controlling agent to modify/control the release of the active ingredient in the finished dosage form.

Description

EXTENDED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING
FESOTERODINE AND PROCESS FOR THE PREPARATION THEREOF
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved extended release dosage form, and in particular to a pharmaceutical composition for oral administration comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite, or derivative thereof, as an active ingredient, and an effective quantity of glycerol dibehenate as stabilizing agent in order to prevent the degradation of said active ingredient, and a process for the preparation thereof.
BACKGROUND OF THE INVENTION
Fesoterodine is a muscarinic receptor antagonist used for the treatment of overactive bladder syndrome including urinary incontinence. Fesoterodine's chemical name is [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropy11-4-(hydroxymethyl)phenyl]2-methylpropanoate) and its chemical structure is presented by the following Formula I.

nac 0 H
HO N 'CHt3, Formula I
Fesoterodine is rapidly hydrolyzed in vivo into its active metabolite 5-hydroxy methyl tolterodine, which binds and inhibits muscarinic receptors on the bladder detrusor muscle, thereby preventing bladder contractions or spasms caused by acetylcholine.
This results in the relaxation of bladder smooth muscle and greater bladder capacity, in addition to a reduction in involuntary muscle contractions and involuntary loss of urine.
Said conversion of fesoterodine into 5-hydroxymethyltolterodine under humid environment and at increased temperature is undesirable in the pharmaceutical formulation.
Therefore, there is a need to provide a pharmaceutical composition comprising fesoterodine that is stable against fesoterodine degradation over an extended period of time.

-2-Furthermore, the dissolution profile of extended release pharmaceutical compositions containing fesoterodine or a pharmaceutical acceptable salt, derivative and metabolite thereof can also be influenced by the selection of the excipients, as the drug release rate is dependent from the gastrointestinal pH-value and/or ionic strength. It is favorable for an extended release formulation to possess drug release rates, independent or less dependent from the ionic strength and/or pH of the environment through out the whole gastrointestinal tract in order to achieve better treatment to a patient.
Various methods are already known for the industrial preparation of extended release oral dosage forms comprising Fesoterodine or a pharmaceutical acceptable salt, derivative and metabolite thereof as an active ingredient due to its useful therapeutical properties. However, the prior art has encountered substantial difficulties in the production of a stable extended release and bioavailable fesoterodine composition of a desirable dissolution profile and a cost effective manufacturing process.
EP-B-2029134 discloses a pharmaceutical granulate comprising fesoterodine or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable stabilizer against hydrolysis, such as sorbitol, xylitol, polydextrose, isomalt, dextrose or combinations thereof. Further, said fesoterodine and stabilizer granulate is embedded in a gel matrix formed by a water swellable sustained release agent such as hydroxypropyl methylcellulose. According to said document, fesoterodine is more stable in a composition comprising sugar alcohols and in the presence of water e.g. by wet granulation. Dry granulation or direct compression resulted in higher amounts of undesirable degradation products.
EP-A-2508175 discloses a microencapsulated fesoterodine composition which is composed of a particle containing fesoterodine and a shell surrounding the fesoterodine-containing particle, wherein the shell comprises a hydrophobic polymer as rate-controlling agent, such as acrylate-based polymers, acrylates or methylacrylates and a pore-forming agent, such as water soluble polymer or water soluble salt. According to said document, in order to prevent degradation of fesoterodine, the proposed composition requires a complex-structured pharmaceutical composition.
Although each of the above patents represents an attempt to achieve a desirable release rate for once a day administration and to overcome the stability problems of the active ingredient associated with pharmaceuticals compositions comprising fesoterodine, there still exists a need for improving fesoterodine's stability of such pharmaceutical compositions in a less complicated production approach.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide an improved sustained release solid dosage composition for oral administration containing fesoterodine or pharmaceutical acceptable salt, derivative or metabolite thereof as an active ingredient, which overcomes the deficiencies of the prior art.
It is another, object of the present invention to provide a stable sustained release solid pharmaceutical composition for oral administration containing fesoterodine or pharmaceutical acceptable salt, derivative or metabolite thereof as an active ingredient, which is safe and effective with sufficient shelf-life and good pharmacotechnical properties.

-3-Moreover, it is another object of the present invention to provide a suitable process for the preparation of an extended release pharmaceutical composition for oral administration .. comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, derivative or metabolite thereof as an active ingredient, which is cost effective and reproducible.
In accordance with the above objects of the present invention, an extended release pharmaceutical composition for oral administration is provided comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite or derivative thereof, as an active ingredient and an effective quantity of glycerol dibehenate as a stabilizing agent in order to prevent the degradation and improve the physicochemical stability of the active ingredient in the finished dosage form.
According to another embodiment of the present invention, a process for the preparation of an extended release pharmaceutical composition for oral administration comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite or derivative thereof as an active ingredient, and an effective quantity of glycerol dibehenate as a stabilizing agent in order to prevent the degradation of said active ingredient is provided, wherein said process comprises following steps:
A. Dispensing: Weight individually the active ingredient and pass it through appropriate sieve.
B. Melting: Weight individually the stabilizing agent Glycerol Dibehenate and melt it at 85 C.
C. Melt Mixing (melt granulation): Add sieved active ingredient from step A to the molten liquid obtained from step B, mix for proper time and allow the granules to cool down D. Sizing: Pass the granules from step C to an appropriate sieve E. Pre- Mixing: Mix the sieved extragranular excipients (Lactose, microcrystalline cellulose, Hydroxypropyl methylcellulose, Talc, colloidal silicon dioxide) and lubricant (Glycerol Dibehenate) for appropriate time.
F. Mixing - Lubrication: Mix the powder resulting from step D with the mixture from step E for appropriate time.
.. G. Compression: Compress the powder resulting from step F into tablets in a rotary compression machine using appropriate punches.
H. Coating: Prepare an aqueous solution/suspension of OpadryTM and coat the tablets from step G.
Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.
Date Regue/Date Received 2022-12-01

-4-BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows dissolution profiles of fesoterodine containing pharmaceutical composition according to the present invention (composition 1) DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, a pharmaceutical composition comprising fesoterodine or salts, metabolites or derivatives thereof is considered to be "stable" if said ingredient degradates less or more slowly than it does on its own and/or in known pharmaceutical compositions during storage.
An excipient is considered to be "incompatible" with fesoterodine or salts, metabolites or derivatives thereof if it promotes the degradation of said active ingredient, that is to say, if said active ingredient degrades more or faster in the presence of said excipient when compared with the degradation of said active ingredient on its own. The terms "incompatibility", "compatible"
and "compatibility" are defined accordingly.
The active ingredient contained in a dosage form is "bioavailable", if when administered in a dosage form is released from the dosage form, absorbed and reaches, at least the same, concentration levels in plasma as any of the marketed products containing the same quantity of the same active ingredient and intended for the same use.
Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.
One of the main disadvantages of fesoterodine or salts, metabolites or derivatives thereof is the fact that, it is very labile and consequently many limitations concerning the choice of excipients are raised.
It has been surprisingly found that the object of the present invention is achieved by employing a glycerol dibehenate as stabilizing agent, in order to prevent the degradation and improve the physicochemical stability of the active ingredient in the finished dosage form.
Further, it has been found that Fesoterodine or salts, metabolites or derivatives thereof comprising glycerol dibehenate as stabilizing agent have very good stability and dissolution characteristics.
Glycerol dibehenate is a glyceride with a high melting point used as a modified release agent, lubricant in tablets, as stabilizer in lipid coating technologies and as lipid carrier for nanoparticles. Glycerol dibehenate is prepared by the esterification of glycerin with behenic acid (C22 fatty acid) without the use of catalysts. In the case of Compritol 888 ATO (Gattefosse), raw materials used are of vegetable origin, and the esterified material is atomized by spraycooling.
Glycerol dibehenate is inert. It does not react with active pharmaceutical ingredients (API) or other excipients. Its inertness is explained by its chemical nature and robust production process:
= It is a lipid excipient with less than 1% of water = It does not have reactive groups = It has very low level of impurity:- low peroxide value, low iodine value As molten lipid excipient in hot melt coating it comes in effect with the solid drug particles in a suitable coating device, it produces a thin, homogeneous film coating that acts as an effective

-5-barrier against water vapor protecting substrate-API from relative humidity/degradation and resolving API compatibility problems. The mechanism of melt granulation is analogous to wet granulation. The initial particle-particle bonds are formed by the surface tension of liquid (molten hot-melt lipid excipient). On subsequent cooling, the molten lipid excipient solidifies forming solid bridges that permanently bind the particles together.
The weight ratio of fesoterodine fumarate to glycerol dibehenate in the solid composition according to the present invention may be selected from 1:0.5 to 1:40.
The pharmaceutical compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients.
According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions (tablet/capsule compositions).
Such ingredients include, but are not limited to, diluents, binders, rate controlling agents, compression aids, glidants, lubricants, water scavengers, colorants, coating agents and preservatives.
The optional excipients must be compatible with fesoterodine or salt, metabolite or derivative thereof so that it does not interfere with it in the composition.
Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the shelf-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability.
The composition of the present invention may include further additives (alone or in a combination) such as absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, p1-1 control agents, plasticizers, retarding agents, stabilizers, suspending agents, thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers etc.
Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 10-90 weight % of the total weight of the composition.
Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene =

-6-oxide, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1-40 weight % of the total weight of the composition.
Rate controlling agents may be selected from one or more polymers/copolymers of cellulose or its derivatives such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, methylcellulose, carboxymethylcellulose and its salts;
polyacrylates, methylacrylates, polyethylene oxides, polyethylene glycols, gums, chitosan, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or its derivatives, ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glycerol dibehenate, polyanhydrides, methylacrylates, polyamides, polycarbonates, polyalkylene, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-glycolides), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methylmethacrylate), poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutyl-methacrylate), poly(hexylmethacrylate), poly(isodecylmethacrylate), poly(lauryl-methacrylate), poly(phenylmethacrylate), poly(methylacrylate), poly (isopropyl-methacrylate) and the like. Rate controlling agents may be in the range of 1-95 weight % of the total weight of the composition.
Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-5 weight % of the total weight of the composition.
Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glycerol dibehenate and the like.
Lubricants may be in the range of 0.01-5 weight % of the total weight of the composition.
All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated.
Another embodiment of the present invention is the use of a hot melt granulation process for the preparation of solid dosage forms for oral administration containing fesoterodine or salt, metabolite or derivative thereof. The steps in this technique may be as follows:
A. Dispensing: Weight individually the active ingredient and pass it through appropriate sieve.
B. Melting: Weight individually the stabilizing agent Glycerol Dibehenate and melt it at 85 C.
C. Melt Mixing (melt granulation): Add sieved active ingredient from step A to the molten liquid obtained from step B, mix for proper time and allow the granules to cool down D. Sizing: Pass the granules from step C to an appropriate sieve E. Pre- Mixing: Mix the sieved extragranular excipients (Lactose, microcrystalline cellulose, Hydroxypropyl methylcellulose, Talc, colloidal silicon dioxide) and lubricant (Glycerol Dibehenate) for appropriate time.

-7-F. Mixing - Lubrication: Mix the powder resulting from step D with the mixture from step E for appropriate time.
G. Compression: Compress the powder resulting from step F into tablets in a rotary compression machine using appropriate punches.
H. Coating: Prepare an aqueous solution/suspension of opadryTm and coat the tablets from step G.
The extended release pharmaceutical composition of the present invention comprising Fesoterodine fumarate as an active ingredient has been compared to extended release reference product Toviairm consisting of fesoterodine fumarate with the following excipients xylitol, Lactose monohydrate, Microcrystalline cellulose, Hypromellose, Glyceroldibehenate (as lubricant), Talc, and as film-coating comprising Poly(vinyl alcohol), Titanium dioxide, Macrogol, Talc, Soya lecithin and indigo carmine aluminium lake.
The pharmaceutical compositions according to the present invention are characterized by .. excellent pharmacotechnical properties, such as homogeneity, flowability and compressibility.
Thanks to these properties, the solid dosage forms prepared by the process according to the present invention exhibit excellent technical characteristics including dissolution rate, hardness, and stability.
One of the most critical pharmacotechnical tests is the Dissolution test as it is strongly correlated with the bioavailability of the product. For the dissolution method a Paddle Apparatus was used at rotation speed 75rpm, in aqueous dissolution medium with pH 6.8.
TABLE 1: Dissolution profile of Composition 1 % Dissolved at p11,6.8 Time (hrs) Composition 1 1 14,8 2 28,2 4 49,0 6 64,1

8 72,7 12 85,6 16 91,5 20 94,9 As it is shown in Table 1, composition 1 according to the present invention shows an extended release of Fesoterodine as depicted in Fig. 1.
One of the main objects of the present invention was to prepare a product with acceptable stability. For this reason composition I was exposed to accelerated (40 C 2 C/75%- 5% RH) stability studies according to the current ICH guidelines.

The stability results are shown in TABLE 2 below.
TABLE 2: Stability results of Composition 1 directly after preparation and after 1 month of storage in aluminium blisters at accelerated conditions Impurities 0 Month 1 Month Accelerated Dial 0.09 0.27 Total 0.15 0.36 The results showed that the stability of the present invention was good.
The selection of appropriate materials (excipients, reagents etc.) should be done carefully in order to avoid any incompatibility problems or non-compliance with European Pharmacopoeia and FDA guidelines for inactive ingredients.
The tablets may be film coated with functional or non-functional coating.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.
EXAMPLES
Example 1: Fesoterodine fumarate Composition 1 according to the present invention Composition 1 of the present invention is illustrated in TABLE 3 below.
TABLE 3: Fesoterodine fumarate Composition 1 Ingredients Composition 1 mg/tab Fesoterodine Fumarate 8.00 Glycerol dibehenate 36.00 Hydroxypropyl 92.00 methylcellulose MicroceLacTM 100 162.30 Aerosil TM 200 3.20 Talc 8.50 Glycerol dibehenate 10.00 Tab Total 320.00 Coating 19.00 Total 339.00 =

-9-Example 2: Fesoterodine fumarate Compositions 2, 3 and 4 according to the present invention Compositions 2, 3 and 4 of the present invention, as illustrated in TABLE 4 below, with different quantities of Glycerol Dibehenate were tested.
Composition 2 comprises Fesoterodine fumarate and Glycerol Dibehenate as stabilizing agent wherein the weight ratio of Fesoterodine fumarate to Glycerol Dibehenate is 1:9.
Composition 3 comprises Fesoterodine fumarate and Glycerol Dibehenate as stabilizing agent wherein the weight ratio of Fesoterodine fumarate to Glycerol Dibehenate is 1:4.5.
Composition 4 comprises of Fesoterodine fumarate and Glycerol Dibehenate as stabilizing agent wherein the weight ratio of Fesoterodine fumarate to Glycerol Dibehenate is 1:18.
TABLE 4: Fesoterodine fumarate Composition 2, 3 and 4 Ingredients Composition 2 Composition 3 Composition 4 mg/tab mg/tab mg/tab Intra - granular Fesoterodine Fumarate 8.0 8.0 8.0 Glycerol dibehenate 72.0 36.0 144.0 Extra - granular Hydroxypropyl 144 0 144.0 144.0 .
methylcellulose MicroceLacTM 100 74.3 110.3 2.3 Aerosil TM 200 3.2 3.2 3.2 Glidant - Lubricant Talc 8.5 8.5 8.5 Glycerol dibehenate 10.0 10.0

10.0 Purified water qs qs qs Tab Weight (mg) 320.0 320.0 320.0 Opadry TM 16.0 16.0 16.0 , Tablets of fesoterodine fumarate of the above Compositions 2, 3 and 4 were prepared according to the following manufacturing process:
At a first stage, fesoterodine fumarate was weighted individually and passed through appropriate sieve. Glycerol dibehenate as stabilizing agent was weighted individually and then, melted at 85 C. The sieved fesoterodine fumarate was added in the molten liquid of the stabilizing agent and mixed for appropriate time until the agglomerates cool down and the melt granulation process is completed with the solidification of the molten stabilizing agent.
Subsequently, the obtained granules were passed through an appropriate sieve.
At a second stage, a mixture of the sieved extragranular excipients was formed by mixing for appropriate time MicroceLacTM 100 as diluent, Hydroxypropyl methylcellulose, as rate =

controlling agent, Talc and colloidal silicon dioxide (Aerosilml 200), as glidants and the quantity of Glycerol Dibehenate, as lubricant.
The powder obtained from the first stage was mixed with the mixture of the second stage until , complete homogeneity. The resulting powder was compressed into tablets in a rotary compression machine using appropriate punches. Then, the tablets were coated with an aqueous solution/suspension of OpadryTm, that was prepared.
Another object of the present invention was to prepare a pharmaceutical composition that is stable for a long period of storage time. Therefore, tablets of Compositions 2, 3 and 4 in closed High-density polyethylene (HDPE) vials were exposed to accelerated (40 C 2 C/75%5% RH) stability studies according to the current ICH guidelines.
The stability results of Compositions 2, 3 and 4 at accelerated conditions, in comparison to the reference product, Toviaz are shown in TABLE 5 below.
TABLE 5: Comparative stability results of Compositions 2, 3 and 4 vs reference product Toviaz Impurities 1Month Reference Composition Composition Composition Closed HDPE
Product 2 3 4 Accelerated 0.97/1.92 0.62/1.32 0.31/0.54 0.48/0.70 (Diol/Total) 0/0 The results showed that the stability of Compositions 2, 3 and 4 of the present invention was improved compared to reference product Toviaz . Particularly, diol content of Compositions 2, 3 and 4 was 0.62%, 0.31% and 0.48%, respectively, compared to reference product wherein diol impurity was 0.97% and total impurities of Compositions 2, 3 and 4 were 1.32%, 0.54% and 0.70%, respectively, compared to reference product wherein total impurities were 01.92%.
In addition, as shown in Fig. 1, Fesoterodine Composition 1 showed extended release of the active ingredient for a time period more than 20h.
Consequently, a novel improved extended release composition of fesoterodine fumarate has been achieved comprising fesoterodine, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable stabilizing agent, wherein said stabilizing agent is glycerol dibehenate. The use of glycerol dibehenate is able to improve the physicochemical stability of the active ingredient in the finished dosage form by protecting said active ingredient from degradation, and maintaining an extended release profile of said active ingredient.
The stability of the product as well as the simple and economic manufacturing process indicates the advantages of the present invention relative to the commonly used method and excipients for the formulation of fesoterodine.
While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

-11-

1. An extended release pharmaceutical composition for oral administration comprising fesoterodine or a pharmaceutically acceptable salt thereof as active ingredient, and an effective quantity of glycerol dibehenate as stabilizing agent in order to prevent degradation and improve the physicochemical stability of the active ingredient in a finished dosage form, which is prepared by hot melt process.

2. The pharmaceutical composition according to claim 1, wherein said active ingredient is fesoterodine fumarate.

3. The pharmaceutical composition according to claim 2, wherein a ratio of the fesoterodine fumarate to the glycerol dibehenate as stabilizing agent by weight is from 1:0.5 to 1:40.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient as rate controlling agent, to modify/control the release of the active ingredient in the finished dosage form.

5. The pharmaceutical composition according to claim 4, wherein the excipient is hydroxypropyl methylcellulose.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the amount of glycerol dibehenate as stabilizing agent in the composition is at least 1% by weight of the total weight of the composition.

7. The pharmaceutical composition according to any one of claims 1-6, wherein said pharmaceutical composition further comprises pharmaceutically acceptable additives selected from a group comprising of absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH
control agents, plasticizers, retarding agents, stabilizers, suspending agents, sweeteners, Date Recue/Date Received 2023-07-04 thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers and their combinations thereof.

8. The pharmaceutical composition according to claim 5, wherein said composition further comprises a diluent, Colloidal Silicon Dioxide and talc as glidants and additional glycerol dibehenate as lubricant.

9. A process for the preparation of an extended release phamiaceutical composition for oral administration comprising fesoterodine or a pharmaceutically acceptable salt thereof as active ingredient, and an effective quantity of glycerol dibehenate as stabilizing agent in order to prevent degradation and improve the physicochemical stability of the active ingredient in a finished dosage form, wherein said process comprises the steps of:
A. Dispensing: Weighing the active ingredient and passing it through a sieve;
B. Melting: Weighing the stabilizing agent glycerol dibehenate and melting it at 85 C to form a molten liquid;
C. Melt Mixing/melt granulation: Adding sieved active ingredient from step A
to the molten liquid obtained from step B to form granules, and allowing the granules to cool down;
D. Sizing: Passing the granules from step C through a sieve to form a powder;
E. Pre-Mixing: Mixing sieved extragranular excipients, lactose and microcrystalline cellulose as diluents, hydroxypropyl methylcellulose as rate controlling agent, talc and colloidal silicon dioxide as glidants, and additional glycerol dibehenate as lubricant to form a mixture;
F. Mixing - Lubrication: Mixing the powder resulting from step D with the mixture from step E for a time to form a second powder;
G. Compression: Compressing the second powder resulting from step F into tablets in a rotary compression machine using punches; and H. Coating: Preparing an aqueous solution/suspension of a pharmaceutically acceptable coating, and coating the tablets from step G.
Date Recue/Date Received 2023-07-04

10. The process for the preparation of a pharmaceutical composition according to claim 9, wherein fesoterocline fumarate is included with the glycerol dibehenate as stabilizing agent in a ratio by weight from 1:0.5 to 1:40.
Date Recue/Date Received 2023-07-04